Associations Between Antidepressant Use and Advanced Diabetes Outcomes in Patients with Depression and Diabetes Mellitus

Context Comorbid depression in patients with diabetes deteriorates the prognosis. Antidepressants might attenuate the adverse effects of depression; however, they are associated with cardiometabolic adverse effects. Objective This study aimed to explore the association between antidepressant treatment and advanced diabetic complications and mortality among patients with depression and diabetes mellitus. Methods We conducted a nationwide retrospective cohort study of 36 276 patients with depression and newly treated diabetes mellitus using Taiwan’s universal health insurance database. Antidepressant treatment patterns within a 6-month window were classified into none, poor, partial, and regular use, and we accounted for time-dependent variables in the Cox proportional hazards regression analysis with adjustment for time-dependent comorbidity and concomitant use of medications. Different classes of antidepressants were compared. Macro- and microvascular complications, as well as all-cause mortality, were the main outcomes. Benzodiazepines were chosen as negative control exposure. Results Compared with poor use of antidepressants, regular use was associated with a 0.92-fold decreased risk of macrovascular complications and a 0.86-fold decreased risk of all-cause mortality but not associated with microvascular complications. Regular use of selective serotonin reuptake inhibitors was associated with a 0.83- and 0.75-fold decreased risk of macrovascular complications and all-cause mortality, respectively. Regular use of tricyclic or tetracyclic antidepressants was associated with a 0.78-fold decreased risk of all-cause mortality. Regular use of benzodiazepine showed no association with diabetic outcomes. Conclusion Regular antidepressant use was associated with lower risk of advanced diabetic complications compared with poor adherence. Clinicians should emphasize antidepressant treatment adherence among patients with depression and diabetes mellitus.

POSSIBLE COMPLICATIONS OF ANTIDEPRESSANTS AND THEIR CORRECTION

Depression and the complications of its pharmacotherapy remain relevant issues in modern medicine. Since the advent of the first antidepressants, more than 60 years ago, to the present, their arsenal has expanded significantly. On the one hand, the emergence of new antidepressants is a great achievement in psychopharmacology, and on the other hand, due to their specificity, antidepressants cause many complications. In addition, in recent years, the list of diseases in which off label (outside the instructions) use these drugs has expanded significantly, and given the fact that for these diseases, anti-depressants are prescribed in combination with other drugs, so the risk of developing side effects increases significantly . This article analyzes the frequently encountered side effects of antidepressants, the mechanisms of their occurrence when using both first-generation antidepressants (three and tetracyclic antidepressants, monoamine oxidase inhibitors) and newer drugs from the group of selective serotonin reuptake inhibitors. The conditions for the rational use of antidepressants are also presented, which allows to optimize their use and the safety of pharmacotherapy for depression. Thus, today it is necessary to create new safer antidepressants that selectively inhibit the reuptake of one of monoamines (for example, serotonin) and third-generation drugs with a “double” effect, i. e. selectively and equipotentially inhibiting the reuptake of serotonin and norepinephrine.

Using Machine Learning Imputed Outcomes to Assess Drug-Dependent Risk of Self-Harm in Patients with Bipolar Disorder: A Comparative Effectiveness Study (Preprint)

BACKGROUND Incomplete suicidality coding in administrative claims data is a known obstacle for observational studies. With most of the negative outcomes missing from the data, it is challenging to assess the evidence on treatment strategies for the prevention of self-harm in bipolar disorder (BD), including pharmacotherapy and psychotherapy. There are conflicting data from studies on the drug-dependent risk of self-harm, and there is major uncertainty regarding the preventive effect of monotherapy and drug combinations. OBJECTIVE The aim of this study was to compare all commonly used BD pharmacotherapies, as well as psychotherapy for the risk of self-harm, in a large population of commercially insured individuals, using self-harm imputation to overcome the known limitations of this outcome being underrecorded within US electronic health care records. METHODS The IBM MarketScan administrative claims database was used to compare self-harm risk in patients with BD following 65 drug regimens and drug-free periods. Probable but uncoded self-harm events were imputed via machine learning, with different probability thresholds examined in a sensitivity analysis. Comparators included lithium, mood-stabilizing anticonvulsants (MSAs), second-generation antipsychotics (SGAs), first-generation antipsychotics (FGAs), and five classes of antidepressants. Cox regression models with time-varying covariates were built for individual treatment regimens and for any pharmacotherapy with or without psychosocial interventions (“psychotherapy”). RESULTS Among 529,359 patients, 1.66% (n=8813 events) had imputed and/or coded self-harm following the exposure of interest. A higher self-harm risk was observed during adolescence. After multiple testing adjustment (<i>P</i>≤.012), the following six regimens had higher risk of self-harm than lithium: tri/tetracyclic antidepressants + SGA, FGA + MSA, FGA, serotonin-norepinephrine reuptake inhibitor (SNRI) + SGA, lithium + MSA, and lithium + SGA (hazard ratios [HRs] 1.44-2.29), and the following nine had lower risk: lamotrigine, valproate, risperidone, aripiprazole, SNRI, selective serotonin reuptake inhibitor (SSRI), “no drug,” bupropion, and bupropion + SSRI (HRs 0.28-0.74). Psychotherapy alone (without medication) had a lower self-harm risk than no treatment (HR 0.56, 95% CI 0.52-0.60; <i>P</i>=8.76×10^-58). The sensitivity analysis showed that the direction of drug-outcome associations did not change as a function of the self-harm probability threshold. CONCLUSIONS Our data support evidence on the effectiveness of antidepressants, MSAs, and psychotherapy for self-harm prevention in BD. CLINICALTRIAL ClinicalTrials.gov NCT02893371; https://clinicaltrials.gov/ct2/show/NCT02893371

Pharmacotherapy of borderline personality disorder: what has changed over two decades? A retrospective evaluation of clinical practice

Background The purpose of this study was to assess the pharmacological treatment strategies of inpatients with borderline personality disorder between 2008 and 2012. Additionally, we compared pharmacotherapy during this period to a previous one (1996 to 2004). Methods Charts of 87 patients with the main diagnosis of borderline personality disorder receiving inpatient treatment in the University Medical Center of Goettingen, Germany, between 2008 and 2012 were evaluated retrospectively. For each inpatient treatment, psychotropic drug therapy including admission and discharge medication was documented. We compared the prescription rates of the interval 2008–2012 with the interval 1996–2004. Results 94% of all inpatients of the interval 2008–2012 were treated with at least one psychotropic drug at time of discharge. All classes of psychotropic drugs were applied. We found high prescription rates of naltrexone (35.6%), quetiapine (19.5%), mirtazapine (18.4%), sertraline (12.6%), and escitalopram (11.5%). Compared to 1996–2004, rates of low-potency antipsychotics, tri−/tetracyclic antidepressants and mood stabilizers significantly decreased while usage of naltrexone significantly increased. Conclusions In inpatient settings, pharmacotherapy is still highly prevalent in the management of BPD. Prescription strategies changed between 1996 and 2012. Quetiapine was preferred, older antidepressants and low-potency antipsychotics were avoided. Opioid antagonists are increasingly used and should be considered for further investigation.

The Effect of Cyp2d6 Gene Polymorphism on the Efficacy and Safety of Mirtazapine in Patients with Depressive Disorders Comorbid with Alcohol

Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder, which adversely affects the prognosis of the course of both diseases. For the treatment of a depressive disorder, drugs from the group of tetracyclic antidepressants, of which mirtazapine is a representative, are used. Therapy with mirtazapine is associated with the risk of undesirable drug reactions and pharmacoresistance. Aim: To study the effect of CYPD6 isoenzyme activity on the efficacy and safety of mirtazapine therapy in patients with depressive disorders comorbid with alcoholism. Methods: The study was conducted on 109 Russian patients with a depressive disorder, comorbid with alcohol dependence. For the correction of depressive disorders within the framework of cyclothymia, mirtazapine was prescribed to patients at a dosage of 1545 mg/day. CYP2D6*4 genotyping (1846G A, rs3892097) was carried out using Real-time polymerase chain reaction with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of adverse drug reactions. Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.8; 5.0] (p0.001), safety indicator, estimated on a UKU scale: (GG) 3.0 [3.0; 3.0], (GA) 4.0 [4.0; 5.0] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [0.8; 3.2] (p0.001), safety indicator, estimated on a UKU scale: (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p0.001). Conclusion: In this study, the effect of CYP2D6 gene polymorphism on the efficacy and safety of therapy with mirtazapine was demonstrated. Carrying a minor allele A is associated with an increased risk of adverse drug reactions, but improving performance profile performance.

Antidepressants Reduced Risk of Mortality in Patients With Diabetes Mellitus: A Population-Based Cohort Study in Taiwan

Context The effect of antidepressant (ATD) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied, although comorbid depression is common in this population. Objective To explore the impact of ATDs on mortality among DM patients. Design A retrospective cohort study in a national database. Setting This population-based study used the National Health Insurance Research Database in Taiwan. Since 2000, we identified 53,412 cases of newly diagnosed patients with DM and depression. Patient cases were followed for assessing mortality until 2013. Main Outcome Measure The association between mortality and ATD use was explored adjusting for cumulative dosing. Results Using the time-dependent Cox regression model, ATD use was associated with significantly reduced mortality among patients with DM [in the highest dose group: hazard ratio (HR), 0.65; 95% CI, 0.59 to 0.71]. Further analysis showed that differences in mortality existed across ATD categories: selective serotonin reuptake inhibitors (HR, 0.63; 95% CI, 0.56 to 0.71), serotonin-norepinephrine reuptake inhibitors (HR, 0.58; 95% CI, 0.44 to 0.78), norepinephrine-dopamine reuptake inhibitors (HR, 0.20; 95% CI, 0.07 to 0.63), mirtazapine (HR, 0.60; 95% CI, 0.45 to 0.82), tricyclic/tetracyclic antidepressants (HR, 0.73; 95% CI, 0.54 to 0.97), and trazodone (HR, 0.52; 95% CI, 0.29 to 0.91). However, reversible inhibitor of monoamine oxidase A (RIMA) was found to be associated with an increase, rather than a decrease, in total mortality (HR, 1.48; 95% CI, 1.09 to 1.99). Conclusion Most ATDs, but not RIMA, were associated with significantly reduced mortality among a population with comorbid DM and depression.